Abstract
Water miscible cosolvents in parenteral products generally increase pain and/or local irritation post injection. The goal of this study was to validate the usefulness of the rat paw lick model (Cleozzi et al., J. Pharmacol. Meth., 4, 1980, 285–289) in screening pain and local irritation with parenteral formulations. Paw licks were counted in 3 min. intervals, over a total period of 15 min., following subplantar injection of test formulations in the hind paw of rats. A dose-response relationship following the injection of solutions containing increasing concentrations of a known painful compound was used to validate the model. The results obtained from additional experiments were found to correlate closely to those obtained using other tests (e.g. in vitro hemoglobin release test, and in vivo creatine kinase release test in rabbits). It was found that: (a) the model is responsive to changes in the sensation of pain and/or irritation due to drug or non-active components; (b) the increase in propylene glycol or ethanol concentrations results in increased pain and/or local irritation, (c) the increase in the apparent pH of cosolvent-based formulations from 7.2 to ≥ 10 may increase pain and/or local irritation, and (d) there is generally a “thresh-hold limit” between the concentration of painful component and the paw licks, which should be established for the component under evaluation. The data overall suggest that the rat paw lick model is a rapid and simple method for rapid screening of formulations for pain/irritation following local administration.
- Received September 15, 1993.
- Accepted December 6, 1993.
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